Expansion of a polyglutamine (polyQ) tract is the basis of several inherited neurodegenerative diseases including spinocerebellar ataxia type 2 (SCA2). Polyglutamine diseases share several features, most importantly, the presence of intranuclear neuronal aggregates in disease brains. However, pathogenesis leading to neurodegeneration in SCA2 may differ in that the pathologic polyQ tracts in ataxin-2, the SCA2 gene product, are relatively short and intranuclear aggregates have not been found. Four hypotheses will be tested: 1) the ER exist motif, clathrin mediated sorting signal and self-association domain in ataxin-2 are functional and are important for pathogenesis. 2) Expression of full- length ataxin-2 in mouse Purkinje cells in vivo causes dysfunction and neurodegeneration. 3) The interaction of ataxin-2 with a novel binding protein, A2BP1, is important for pathogenesis. 4) Proteolytic cleavage of ataxin-2 increases pathogenesis. To evaluate these hypotheses two specific aims are proposed: In the first aim, cultured cells and human tissues will be used to determine the subcellular localization and proteolytic processing of normal and mutated ataxin-2. The consequences of deleting specific domains will be analyzed. The interaction of A2BP1with ataxin-2 will be characterized, especially as it relates to the self-interaction of ataxin-2. Studies in the second aim will determine which domains in ataxin-2 are necessary for pathogenesis in vivo. Based on the results in aim 1, transgenic mice expressing ataxin-2 with normal and pathologic polyQ tracts will be generated, as well as mice expressing ataxin-2 with deletions or point mutations in specific domains. Mice will be compared on tests of motor ability. The deletion of point mutations in specific domains. Mice will be compared on tests of motor ability. The extent of changes in cerebellar Purkinje cells will be examined with anatomical techniques. The ultimate goal of this proposal is to define the necessary molecular components of SCA2 pathogenesis and to contribute to the understanding of neurodegenerative diseases in general.